Auditory Neuroprotection by Small Molecule Agonists of the TrkB Receptor

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DESCRIPTION (provided by applicant): Exogenous application of neurotrophins rescues spiral ganglion (SG) neurons from degeneration resulted from the loss of cochlear hair cells. Since the survival of SG neurons is the basis for cochlear implants to work, these encouraging results have stimulated enormous interest in translation-oriented research aiming at applying exogenous neurotrophin(s) to the human cochlea to promote the survival of residual SG neurons in the cochlea of severe sensorineural hearing loss patients. However, none of these studies have advanced to the phase of clinical trials twelve years after the first series of papers were published. One of the major hurdles hindering the clinical translation is how to achieve long-term, recurring and safe deliveries at desired dosage into the cochlea. We have recently identified a number of high-potency small mimetic molecules of brain derived neurotrophic factor. These compounds readily crossed the blood brain barrier and into the cochlea. They activated TrkB receptors at extremely low concentrations. One of the most potent compounds, 7,8- dihydroxyflavone (7,8-DHF), effectively activated the TrkB receptor at less than 100 nM. The compound also demonstrated effective neuroprotective effects in a number of in vivo models. Most relevant to this project, we have obtained preliminary data showing that systemic application of 7,8-DHF by intraperitoneal injections dramatically protected SG neurons from degeneration without any obvious side effects in mice. The data were acquired from a mouse model of human deafness caused by connexin26 (Cx26) mutations, which is the most common cause of prelingual non-syndromic deafness in humans. These results raise the hope of overcoming the major hurdle of drug delivery for the translation of the auditory neuroprotective effect to benefit patients. This grant seeks support to test the efficacy of 7,8-DHF in both in vitro assay and in vivo animal models, and to conduct preclinical trials for the compound to determine its toxicity and pharmacokinetics. By finishing the specific aims proposed in the project, we will be able to collect crucial preclinical data required for filing an investigational new drug (IND) application with the food and drug administration (FDA) at the end of the funding period. This grant seeks support to test the efficacy of 7,8-DHF in both in vitro assay and in vivo animal models, and to conduct preclinical trials for the compound to determine its toxicity and pharmacokinetics. Our specific aims are: Specific aim 1: We will perform in vitro tests of 7,8-DHF to determine its efficacy in promoting the survival of SG neurons cultured in defined media. We will also test whether 7,8-DHF and depolarization have synergistic effects on the survival of SG neurons in vitro. Specific aim 2: Test the efficacy of 7,8-DHF in vivo for protecting SG neurons against degeneration in conditional Cx26 null mouse models. Specific aim 3: Test the efficacy of 7,8-DHF in vivo for protecting SG neurons against degeneration in a guinea pig model deafened by ototoxic drugs. Specific aim 4: In this specific aim we will perform FDA required preclinical trials for the compound, 7,8-DHF, to obtain organ targeting, toxicity, systemic side effects and pharmacokinetic information for the drug. By finishing these specific aims, we will be able to collect crucial preclinical data required for filing an investigational new drug (IND) application with the food and drug administration (FDA) at the end of the funding period.